Sleep Fragmentation and Alzheimer’s Disease

慢性睡眠中断，由工作时间表，噪音暴露，家庭义务，睡眠障碍，或 生活方式的选择，是当代生活的一个普遍特征。睡眠问题影响高达40%的AD患者， 可能比认知障碍早十多年，并随着疾病的进展而恶化。以及 影响情绪和健康，睡眠中断可能会导致AD神经病理学的发展，例如， 通过减少淀粉样蛋白-β（A β）的清除和促进神经毒性促炎状态， 星形胶质细胞和小胶质细胞。睡眠中断可能包括总睡眠减少（睡眠限制[SR]），深度睡眠丧失， 睡眠（也称为慢波睡眠[SWS]，以大幅度、低频电活动为标志）， 和睡眠片段（SF）为较短的发作。日常睡眠-觉醒节律的碎片化与 老年人患AD的风险更大，认知能力下降更早。尽管这些相关 然而，尽管有许多研究表明慢性SF是否或如何影响AD的进展，但尚未进行实验研究。 与传统的SR方法相比，SF可能是与AD相关的睡眠中断的更好模型。 AD小鼠模型的研究表明，自发发生的SF与更严重的A β相关 实验诱导的SF导致A β蓄积和神经炎症。除了 SF，SWS的丧失可能会加重AD，改善SWS可能对轻度认知障碍有益 (MCI)甚至在AD。由于睡眠中断会对AD相关神经病理学的发展产生不利影响， 令人惊讶的是，巩固睡眠和增加SWS的睡眠增强（SE）策略并没有被 充分探索以减缓或逆转这些影响。我们的总体工作假设是， 睡眠质量，尤其是睡眠碎片和SWS的丧失，比睡眠量更重要。 此外，我们假设这些作用的机制主要是神经炎症，至少在 部分由A β肽沉积介导。我们将使用一种独特的、特征良好的小鼠模型， AD相关A β病理学、神经炎症和认知缺陷。该项目有三个具体目标：（1） SF将加速（SE减慢）AD进展;（2）A β蓄积增加介导 SF诱导的神经炎症、神经病理学和认知能力下降;以及（3）增加 神经炎症介导SF诱导的神经病理学和认知下降。我们将使用多个小说 方法，包括热中性温度操纵，和一种独特的抗炎化合物， 最近进入了早期临床试验阶段。因此，这些研究将阐明潜在的机制， 睡眠中断与AD有关，并将为新的治疗策略奠定基础。

Chronic sleep disruption, resulting from work schedules, noise exposure, family obligations, sleep disorders, or lifestyle choices, is a pervasive feature of contemporary life. Sleep problems affect up to 40% of AD patients, may precede cognitive impairments by more than a decade, and worsen as the disease progresses. As well as affecting mood and well-being, sleep disruption may drive the development of AD neuropathology for instance, by reducing clearance of amyloid-β (Aβ) and by promoting a neurotoxic proinflammatory state involving astrocytes and microglia. Sleep disruption can include reduced total sleep (sleep restriction [SR]), loss of deep sleep (also known as slow-wave sleep [SWS], marked by large amplitude, low frequency electrical activity), and fragmentation of sleep (SF) into shorter bouts. Fragmentation of the daily sleep-wake rhythm is associated with greater risk of incident AD and earlier cognitive decline in older humans. In spite of these correlative studies, whether or how chronic SF impacts the progression of AD has not been experimentally investigated. SF may be a better model of the sleep disruption associated with AD than the traditional approach of SR. Our studies of AD mouse models show that spontaneously occurring SF is associated with more severe Aβ accumulation and that experimentally-induced SF leads to Aβ accumulation and neuroinflammation. Besides SF, loss of SWS may exacerbate AD, and improving SWS may be beneficial in mild cognitive impairment (MCI) or even in AD. Since sleep disruption adversely affects the development of AD-related neuropathology, it is surprising that sleep enhancement (SE) strategies to consolidate sleep and increase SWS have not been adequately explored to slow or reverse these effects. Our overall working hypothesis is that a change in the quality of sleep, especially sleep fragmentation and loss of SWS, is more important than the quantity of sleep. Further, we hypothesize that the mechanism underlying these effects is primarily neuroinflammation, at least in part mediated by Aβ peptide deposition. We will use a unique, well-characterized mouse model, that exhibits AD-related Aβ pathology, neuroinflammation, and cognitive deficits. This project has three specific aims: (1) that SF will accelerate (and SE decelerate) AD progression; (2) that increases in Aβ accumulation mediates SF-induced neuroinflammation, neuropathology, and cognitive decline; and (3) that increases in neuroinflammation mediate SF-induced neuropathology and cognitive decline. We will use multiple novel approaches, including thermoneutral temperature manipulation, and a unique anti-inflammatory compound that has recently entered early stage clinical trials. Thus, these studies will elucidate the underlying mechanisms by which sleep disruption is linked to AD and will lay the groundwork for new therapeutic strategies.